Certain dihydrobenzofuran butanoic and pentanoic acid derivatives

ABSTRACT

Compounds of the general formula I ##STR1## in which R 1  and R 2 , which may be identical or different, each denote a hydrogen atom, a benzyl radical, a cyclohexylmethyl radical or a linear or branched alkyl radical containing from 1 to 10 carbon atoms, optionally substituted with a hydroxy radical, with a carboxy radical or with an alkoxy radical having 1 to 5 carbon atoms, with an alkoxycarbonyl radical having 2 to 6 carbon atoms, with an alkylphenyl radical having 7 to 16 carbon atoms or with a 2-alkylthienyl radical having 5 to 14 carbon atoms, 
     R 3  denotes a hydrogen atom or a linear or branched alkyl radical containing from 1 to 4 carbon atoms, 
     A denotes a single bond or a methylene radical, or a radical of formula ##STR2##  in which R 4  is a linear or branched alkyl radical containing from 1 to 4 carbon atoms. These products are useful in anti-depressant, anti-aggressive, or dopaminergic modulation therapy and the corresponding bicyclic compounds are useful as intermediates for ring closure and production of the tricyclic compounds having the foregoing formula.

This is a division of application Ser. No. 173,286, filed Mar. 25, 1988,now U.S. Pat. No. 4,851,429.

The present invention relates to new tricyclic amines derived from2,3,5,6,7,8-hexahydronaphtho[2,3-b]-furan and from2,3,6,7,8,9-hexahydro-5H-benzocyclohepta[2,3-b]-furan, the processes forpreparing them and the pharmaceutical compositions which contain them.

Some pharmacologically active tricyclic compounds derived fromaminotetrahydronaphthalene are known. In effect, a few compounds of7,8,9,10-tetrahydrobenzo[h]quinol-9-ylamine, whose antidepressantactivity has been assessed only by in vitro tests, are mentioned in theliterature (U.S. Pat. No. 4,521,423).6,7,8,9-Tetrahydrobenzo[g]indol8-ylamines and6,7,8,9-tetrahydronaphtho[1,2-b]furan8-ylamines endowed withdopaminergic stimulatory activity are described in U.S. Pat. Nos.4,510,157 and 4,470,990.

The Applicant has now discovered that some tricyclic amines derived from2,3,5,7,8-hexahyronaphtho [2,3-b]furan or from2,3,6,7,8,9-hexahydro-5H-benzocyclohepta[2,3,-b]furan of novel structurepossess very advantageous pharmacological properties. in effect, thecompounds of the present invention possess dopaminergic properties andconsiderable antidepressant, antiaggressive and psychostimulatoryactivity, demonstrated by in vivo trials.

The subject of the present invention is, more especially, the compoundsof general formula I ##STR3## in which, R₁ and R₂, which may beidentical or different, each denote a hydrogen atome, a benzyl radical,a cyclohexylmethyl radical or a linear or branched alkyl radicalcontaining from 1 to 10 carbon atoms, optionally substituted with ahydroxy radical, with a carboxy radical or with an alkoxy radical having1 to 5 carbon atoms, with an alkoxycarbonyl radical having 2 to 6 carbonatoms, with an alkylphenyl radical having 7 to 16 carbon atoms or with a2-alkylthienyl radical having 5 to 14 carbon atoms,

R₃ denotes a hydrogen atom or a linear or branched alkyl radicalcontaining from 1 to 4 carbon atoms,

A denotes a single bond or a methylene radical, or a radical of formula##STR4## in which R₄ is a linear or branched alkyl radical containingfrom 1 to 4 carbon atoms, in racemic form or in the form of opticalisomers, and their addition salts with a pharmaceutically acceptableinorganic or organic acid.

The subject of the present invention is also the process for preparingthe compounds of general formula I, wherein 2,3-dihydrobenzofuran offormula II ##STR5## is condensed in the presence of a chlorinatedorganic solvent and aluminum chloride with an aspartic or glutamicanhydride derivative of general formula III ##STR6## in which themeaning of A and R₃ is identical to that given for the formula I and Zdenotes a hydrogen or fluorine atom, to form the compounds of generalformula IV ##STR7## in which R₃, A and Z have the meaning stated above,which is reduced in the heated state with triethylsilane in the presenceof trifluoroacetic acid to form the compounds of general formula V##STR8## in which R₃, A and Z have the meaning stated above, which issubjected in the heated state to the action of phosphorus pentoxide inthe presence of phosphoric acid to form the compounds of general formulaVI ##STR9## in which the meaning of R₃, Z and A is that stated above,which is subjected to a catalytic hydrogenation at room temperature inacid medium and in the presence of palladium on charcoal (5% palladium)to obtain an amide of general formula VII ##STR10## in which R₃, A and Zhave the meaning state above, which is reacted with a strong base toobtain a compound of general formula I in which R₁ and R₂ are identicaland each denote a hydrogen atom, which then can be alkylated to form thecorresponding second or tertiary amines,

either by condensing it with a compound of general formula VIII##STR11## in which R' and R", which may be identical or different, eachdenote a hydrogen atom or a lower alkyl radical having 1 to 4 carbonatoms, R"' denotes a lower alkyl radical having 1 to 5 carbon atoms andn in an integer from 0 to 9, to form a compound of general formula I inwhich R₁ denotes a hydrogen atom and R₂ denotes a linear or branchedalkyl radical containing from 1 to 10 carbon atoms, substituted with analkoxycarbonyl radical having 2 to 6 carbon atoms, which can then besubjected to the action of a strong inorganic base to form a compound ofgeneral formula I in which R₁ denotes a hydrogen and R₂ denotes a linearor branched alkyl radical having 1 to 10 carbon atoms, substituted witha carboxy radical,

or by reacting it with an acid chloride of general formula IX

    W(CH.sub.2).sub.n COCl                                     (IX)

in which n is an integer from 0 to 9 and W denotes a phenyl radical or a2-thienyl radical, and then reducing the compound resulting from thisreaction with a double metal hydride to form a compund of generalformula I in which R₁ denotes an alkyl radical having 1 to 10 carbonatoms, substituted with a phenyl radical or a 2-thienyl radical, and R₂is a hydrogen,

or by reacting it with an appropriate quantity of formaldehyde andformic acid to obtain the compounds of general formula I in which R₃ andR₄ are identical and each denote a methyl radical,

or by reacting it with an alkyl iodide of general formula X

    IR                                                         (X)

which R denotes a linear or branched alkyl radical containing from 1 to10 carbon atoms (optionally substituted with a hydroxy radical or withan alkoxy radical having 1 to 5 carbon atoms, or a cyclohexylmethylradical, in the heated state in an organic solvent in the presence of aninorganic base, to form the compounds of general formula I in which R₁and R₂ are identical and have the same meaning as R,

or by subjecting it to the action of benzaldehyde in the heated stateand in the presence of a low molecular weight alcohol to form thecorresponding benzylimine, and then to a catalytic hydrogenationfollowed by the action of formic acid and formaldehyde to form thecompounds of general formula I in which R₁ denotes a methyl radical andR₂ a cyclohexylmethyl radical,

or by subjecting it first to the action of benzaldehyde in the presenceof an inert and apolar aromatic solvent and then, after removal of thesolvent used, to the action of sodium borohydride in the presence of alow molecular weight polar aliphatic alcohol, to obtain a compound ofgeneral formula I in which R₁ denotes a hydrogen and R₂ a benzylradical, which then can be subjected:

either to the action of formaldehyde and formic acid to form thecompounds of general formula I in which R₁ denotes a methyl radical andR₂ a benzyl radical,

or to the action of an alkyl iodide of general formula X to form thecompounds of general formula I in which R₁ has the same meaning as R andR₂ denotes a benzyl radical, which then can be subjected to a catalytichydrogenation to form the compounds of general formula I in which R₁ hasthe meaning given above and R₂ denotes a hydrogen atom, which then canbe subjected to the action of an alkyl iodide of general formula X toform the compounds of general formula I in which R₁ and R₂, which may beidentical or different, each denote an alkyl radical containing from 1to 10 carbon atoms (optionally substituted with a hydroxy radical or analkoxy radical having 1 to 5 carbon atoms) or a cyclohexylmethylradical, which can then, if so desired, be salified with apharmaceutically acceptable inorganic or organic acid, or be separatedinto their optical isomers and then salified.

Different compounds of general formula III are obtained by reactingacetic anhydride or trifluoroacetic anhydride with aspartic or glutamicacid or their analogues substituted with an alkyl at the β- orγ-position. The reaction is carried out first at a temperature belowzero, and then at a temperature of between 30° and 60° C., according tothe method described by BARKER C. C. in J. Chem. Soc. (1953), p.453.

The aspartic acid derivatives containing an alkyl chain at thebeta-position are obtained according to the method described by DAKIN H.D. in J. Biol. Chem. (1941), 141, p.945:950.

The methods of synthesis of the glutamic acid derivatives substitutedwith an alkyl at the β- or γ-position are also known (Gershon H,Parmegiani R, Giannasio V and Krull J., J. Pharm. Scien., (1975), 64,No. 11, p.1855-1858).

The compounds of general formula I can be separated into their opticalisomers after forming the salts with d- and l-camphorsulfonic acids.

Among pharmaceutically acceptable acids for preparing the addition saltswith the compounds of general formula I, hydrochloric, phosphoric,fumaric, citric, oxalic, sulfuric, tartaric, maleic, mandelic andmethanesulfonic acids, and the like, may be mentioned.

The compounds according to the invention, as well as their salts andtheir optical isomers, are endowed with highly advantageouspharmacological properties.

In effect, in vivo pharmacological trials have shown that the compoundspossess potent antidepressant, antiaggressive and psychostimulatoryproperties. These properties have been demonstrated by means of testsclassically used in animals, enabling the activity in man to bepredicted with very great accuracy ("Antidepressants: NeurochemicalBehavioral and Clinical Perspectives" Enna S. J., Malick J., RichelsonE., Raven Press E., 1981, N.Y. and "Industrial Pharmacology,Antidepressants II", Fielding Stuart, Harbans Lal, Futura PublishingComp. Ed., 1975, N.Y.).

The antiaggressive effects of the compounds of the invention wereinvestigated by two methods. The first permitted an assessment of theinhibition of aggressive behavior in previously isolated mice(Charpentier J. "Analysis and measurement of aggressive behavior inmice", Aggressive Behavior, Garattini S. and Sigg E. B. Ed., p.86-100,Excerpta Medica Found. Amsterdam, 1969), and the second, the inhibitionof aggression in isolated and bulbectomized rats (Karli P, Vergnes M.,and Didiergeorges F, "Rat mouse interspecific aggressive behavior andits manipulation by brain ablation and by brain stimulation", AggressiveBehavior, Garrattini S. and Sigg E. B. Ed., p.47-55, Excerpta MedicaFound. Amsterdam, 1969).

The compounds of the invention inhibit isolation-induced aggression inmice and aggression in isolated, bulbectomized rats. The effective dosesare between 3 and 5 mg.kg⁻¹, administered intraperitoneally.

The antidepressant effects of the compounds of the invention wereinvestigated, employing the methods of antagonism of reserpine-inducedhypothermia and antagonism of the ponto-geniculo-occipital waves inducedby the compound Ro4-1284 in cats.

The tests for assessing the antagonism of reserpine-induced hypothermiawere carried out on Swiss CD male mice. After distribution of theanimals into groups, reserpine was injected intraperitoneally at a doseof 2.5 mg.kg⁻¹. Three hours later, the compounds of the vention wereadministered by the same route. The rectal temperature of the animalswas measured 1 hour and 2 hours after the second treatment, and comparedwith the initial temperature of these same animals measured immediatelybefore the administration of the compounds undergoing testing. At themeasurement time 2 hours after the administration, the compounds of theinvention, at a dose of 2.5 mg.kg⁻¹ i.p., antagonize thereserpine-induced hypothermia to the extent of approximately 60%.

For assessing the antagonism of the ponto-geniculo-occipital P.G.O.waves induced by Ro4-1284 in cats, the method described by Ruch-MonachonM. A., Jalfre m. and Haefely W. (Arch. Int. Pharm. Therap., (1976), 219,No.2, p.251-346) was used.

The compounds of the invention strongly antagonize the P.G.O. wavesinduced in cats by the compound Ro4-1284, which depletes cerebralmonoamines. For some of the compounds of the invention subjected to thistest, the (i.v.) effective doses inhibiting by 50% the P.G.O. wave ratio(ED₅₀) are of the order of 0.14 to 0.20 mg.kg⁻¹.

The results of the pharmacological studies demonstrated that thecompounds of the invention have a dopaminergic action, and moreespecially a dopamine-stimulating activity. This activity was assessedby the test of drug discrimination in rats, the general principles ofwhich are stated in "Drug discrimination, application in C.N.S.Pharmocology", F. Colpaert Ed., Elsevier Biomedical, 1982, Amsterdam. Ata dose of 2.5 mg.kg⁻¹, administered intrperitoneally, the compounds ofthe invention behave like apomorphine in the drug discrimination test,which proves that they have a dopaminergic action of an agonist nature.This activity is more pronounced when dextrorotatory isomers of thecompounds of the invention are used for the test. Recently, it has beenfound that, in Parkinson's disease, there is a dopamine depletion of thecentral gray nuclei of the extrapyramidal system. Thus, dopaminergicagonists, like the compounds of the present invention, can have veryadvantageous therapeutic effects for the symptomatic treatment of thisdisease (Burgers Medicinal Chemistry 4th Ed., Part III, p.413-430,(1981) J. Wiley and Sons Ed.). Dopamine also exerts a potent restrainingeffect on the secretion of prolactin, a hormone whose principle actionis the development and maintenance of lactogenesis. The compounds of thepresent invention can hence also be used for treating neuroendocrinedisorders due to a dopaminergic deficiency, such as hyperprolactinemiaand galactorrhea (The Pharmacological basis of Therapeutics, 7th Ed.,p.1374-1385), Goodman Gilman A. Ed., Macmillan Publish. Comp. NY).

The invention also encompasses the pharmaceutical compositionscontaining, as active principle, at least one compound of generalformula I, one of its isomers or one of its salts with apharmaceutically compatible inorganic or organic acid, in combinationwith one or more inert and suitable excipients.

The pharmaceutical compositions thereby obtained are advantageouslypresented in various forms such as, for example, tablets, dragees,gelatin capsules, sublingual tablets or other galenical preparationssuitable for sublingual administration, suppositories, injectablesolutions or solutions to be taken by mouth.

The dosage can vary widely according to the patient's age and weight,the nature and severity of the condition and also the administrationroute.

The preferred administration route is the oral or parenteral route.

Generally speaking, the unit dosage will range between 0.5 and 100 mg,and the daily dosage, usable in human therapy, between 10 and 100 mg.

The examples which follow, given without implied limitation, illustratethe invention.

The melting points are measured according to the micro-Kofler technique.The proton nuclear magnetic resonance (NMR) spectra were recorded at 60MHz.

EXAMPLE 1 N-Trifluoroacetylaspartic anhydride

0.49 mole of aspartic acid is cooled to -10° C. and 1.23 mole oftrifluoroacetic anhydride is added dropwise while the temperature ismaintained at -10° C. The reaction mixture is allowed to return to roomtemperature and is brought gradually to reflux for 2 hours. It iscooled, stirred in the presence of hexane and filtered. The solidresidue obtained is dried.

Yield: 99%.

Melting point: 137°-138° C.

EXAMPLE 2 dl-7-Amino-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan STAGE A4-(2,3-Dihydro-5-benzofuranyl)-4-oxo-2-trifluoroacetamidobutanoic acid

0.1 mole of the compound obtained in Example 1 and 0.05 mole of aluminumchloride suspended in 100 ml of dichloroethane are added to a solutionof 12 ml of dichloroethane containing 0.05 mole of2,3-dihydrobenzofuran. The mixture is stirred for 36 hours at roomtemperature and then hydrolyzed with saturated ammonium chloridesolution. The mixture is extracted with dichloromethane and the extractwashed with water, dried over magnesium sulfate, filtered andconcentrated to obtain the expected product.

Yield: 88%.

Melting point: 160°-162° C.

STAGE B 4-(2,3-Dihydro-5-benzofuranyl)-2-trifluoroacetamidobutanoic acid

0.25 ml of triethylsilane is introduced into a solution of 97 ml oftrifluoroacetic acid containing 0.063 mole of the compound obtained inthe preceding stage. The reaction medium is brought to reflux for 2hours and then poured onto ice. The mixture is extracted with ether. Theorganic phase is washed with water and then dried over anhydrousmagnesium sulfate. It is concentrated under reduced pressure (0.5mm/Hg). The residue is dried under vacuum over phosphorus pentoxide andpotassium hydroxide.

The product is crystallized in a mixture of chloroform, toluene andhexane (20:20:80 V/V) to obtain pure4-(2,3-dihydro-5-benzofuranyl)-2-trifluoroacetamidobutanoic acid.

Yield: 82%.

Melting point: 125° C.

STAGE C7-Trifluoroacetamido-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan-8-one 712g of phosphorus pentoxide are added to 456 ml of 80% strength phosphoricacid. After the mixture is heated for 2 hours at 100° C., thetemperature is allowed to return to 60° C. and 0.09 mole of4-(2,3-dihydro-5-benzofuranyl)-5-trifluoroacetamidobutanoic acid,obtained in the preceding stage, is added. The reaction medium isstirred vigorously for one hour, then cooled and poured into watercontaining ice. The mixture is extracted with ether. The organic phaseis washed with 10% strength aqueous sodium bicarbonate solution and thenwith saturate sodium chloride solution.7-Trifluoroacetamido-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan-8 -one isobtained after drying the ether phase over anhydrous sodium sulfate andevaporation under reduced pressure. The compound is then recrystallizedin acetonitrile.

Yield: 40%.

Melting point: 208° C.

STAGE D 7-Trifluoroacetamido-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan

Approximately 0.07 mole of the compound obtained in the preceding stageis dissolved in a mixture of 100 ml of acetic acid and 2 ml of 70%strength perchloric acid. Reduction is performed under a pressure of 5kg/cm² of hydrogen in the presence of 1 g of palladium on charcoal (5%palladium), and the mixture is then filtered and concentrated underreduced pressure. The residue is taken up with water. The aqueous phaseis separated and the organic phase is dried over anhydrous magnesiumsulfate and concentrated. The product is recrystallized in isopropylether to obtain pure7-trifluoroacetamido-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan.

Yield: 55%.

Melting point: 131° C.

STAGE E

The amide obtained in the preceding stage is brought to reflux for 18hours with 25 ml of 4N hydrochloric acid. After being cooled, thereaction medium is alkalinized and extracted with dichloromethane. Afterdrying and evaporation, 7-amino-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furanis obtained.

Melting point: 60° C.

After the amine thereby obtained has been dissloved in ethyl acetate, anappropriate quantity of ethereal hydrogen chloride is added slowly andwith stirring to obtain the corresponding hydrochloride.

Melting point: 275° C.

NMR spectrum (CDCl₃ +DMSO-d₆): 1.7 to 3.7 ppm, m, 9H; 4.6 ppm, t, 2H;6.5 ppm, m, 1H; 7 ppm, m, 1H; 8.65 ppm, 3H, exchangeable.

EXAMPLE 3 7-Amino-6-methyl-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan

This compound may be prepared according to the process described inExample 2, but using 3-methyl-N-trifluoroacetylaspartic anhydride inStage A. The latter compound may be prepared according to the processdescribed in Example 1. The preparation of the corresponding acid isdescribed in J. Biol. Chem., (1941), 141, p. 945-950.

EXAMPLE 4 8-Amino-2,3,6,7,8,9-hexahydro-5H-benzocyclohepta[2,3-b]furan

This compound may be prepared according to the process described inExample 2, but using N-trifluoroacetylglutamic anhydride instead ofN-trifluoroacetylaspartic anhydride in Stage A.

EXAMPLE 58-Amino-7-methyl-2,3,6,7,8,9-hexahydro-5H-benzocyclohepta[2,3-b]furan

This compound may be prepared from 3-methyl-N-trifluoroacetylglutamicanhydride and according to the process described in Example 2. The3-methylglutamic acid needed for the synthesis of the abovementionedanhydride may be prepared according to the process described in J.Pharm. Scien., (1975), 64, No. 11, p.1855-1858.

EXAMPLE 68-Amino-6-methyl-2,3,6,7,8,9-hexahydro-5H-benzocyclohepta[2,3-b]furan

This compound may be prepared by condensing4-methyl-N-trifluoroacetylglutamic anhydride with 2,3-dihydrobenzofuranaccording to the process described in Example 2. The synthesis of4-methylglutamic acid is known (J. Pharm. Scien., (1975), 64, No. 11,p.1855-1858).

EXAMPLE 7 d-7-Amino-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furancamphorsulfonate

This salt was obtained by reacting the compound of Example 2 with anequimolar quantity of d-camphorsulfonic acid. After tworecrystallizations in ethanol followed by two rectrystallizations inmethanol, the salt is obtained optically pure.

(Estimation by HPLC: >99%).

Melting point: 253°-261° C.

Rotatory power of a 0.5% strength solution in water:

    ______________________________________                                                     23° C.                                                                 [α]                                                                λnm                                                                         D                                                                ______________________________________                                                589  +41.3°                                                            578  +43.3°                                                            546  +51.1°                                                            436  +105.6°                                                           365  +235.0°                                                   ______________________________________                                    

EXAMPLE 8 l-7-Amino-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furancamphorsulfonate

This compound was obtained according to the process described in Example7, but using l-camphorsulfonic acid.

Melting point: 254°-265° C.

Rotatory power of a 0.5% strength solution in water:

    ______________________________________                                                     23° C.                                                                 [α]                                                                nm   D                                                                ______________________________________                                                589  -49.1°                                                            578  -51.4°                                                            546  -60.3°                                                            436  -125.0°                                                           365  -276.4°                                                   ______________________________________                                    

EXAMPLE 9 d-7-Amino-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furanhydrochloride

The compound of Example 7 is dissolved in ethyl acetate and the mediumis then alkalinized with sodium hydroxide. The organic phase isseparated, dried over anhydrous sodium sulfate and evaporated. The oilobtained is taken up in acetonitrile, and a stoichiometric quantity ofethereal hydrogen chloride is then added, to obtain optically pured-7-amino-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan hydrochloride.

Melting point: 261°-264° C.

Rotatory power of a 0.25% strength solution in DMSO:

    ______________________________________                                                     23° C.                                                                 [α]                                                                λnm                                                                         D                                                                ______________________________________                                                589  +86.4°                                                            578  +90.4°                                                            546  +104.4°                                                           436  +191.6°                                                           365  +350.2°                                                   ______________________________________                                    

EXAMPLE 10 l-7-Amino-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furanhydrochloride

This compound was obtained from the compound of Example 8 and accordingto the process described in Example 9.

Melting point: 262°-264° C.

Rotatory power of a 0.25% strength solution in DMSO:

    ______________________________________                                                     23° C.                                                                 [α]                                                                λnm                                                                         D                                                                ______________________________________                                                589  -86.4°                                                            578  -90.4°                                                            546  -104.4°                                                           436  -191.6°                                                           365  -350.2°                                                   ______________________________________                                    

PHARMACEUTICAL PREPARATION EXAMPLE 11 Tablets containing a 25-mg dose ofd-7-amino-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan hydrochloride

    ______________________________________                                        d-7-Amino-2,3,5,6,7,8-hexahydronaphtho[2,3-b]-                                furan hydrochloride      25.00    g                                           wheat starch             100.00   g                                           cornstarch               80.00    g                                           magnesium stearate       15.00    g                                           talc                     20.00    g                                           for 1,000 tablets containing 25 mg of active principle.                       ______________________________________                                    

We claim:
 1. A compound of formula IV ##STR12## in which R₃ denotes ahydrogen atom or a linear or branched alkyl radical containing 1 to 4carbon atoms, inclusiveA denotes a single bond or a methylene radical,or a radical of formula ##STR13## in which R₄ denotes a linear orbranched alkyl radical containing 1 to 4 carbon atoms, inclusive and Zdenotes a hydrogen atom or a fluorine atom.
 2. A compound of claim 1being 4-(2,3-dihydro-5-benzo-furanyl)-4-oxo-2-trifluoroacetamidobutanoicacid.
 3. A compound of formula V ##STR14## in which R₃ denotes ahydrogen atom or a linear or branched alkyl radical containing 1 to 4carbon atoms, inclusiveA denotes a single bond or a methylene radical,or a radical of formula ##STR15## in which R₄ denotes a linear orbranched alkyl radical containing 1 to 4 carbon, inclusive and Z denotesa hydrogen atom or a fluorine atom.
 4. A compound of claim 3 being4-(2,3-dihydro-5-benzofuranyl)-2-trifluoroacetamidobutanoic acid.